This invention is generally in the field of methods and devices for the controlled delivery of parathyroid hormone (PTH) to patients, for example, to promote the growth and maintenance of bone tissue.
The mechanism of bone loss is not completely understood, but the disorder effectively arises from an imbalance in the formation of new healthy bone and the resorption of old bone. The bone loss includes a decrease in both mineral content and protein matrix components of the bone, and leads to an increased rate of bone fracture. These fractures, predominantly femoral bones and bones in the forearm and vertebrae, lead to an increase in general morbidity and a loss of stature and mobility, as well as an increase, in many cases, in mortality caused by complications from the fracture.
Bone loss occurs, for example, in post-menopausal women, patients who have undergone hysterectomy, patients undergoing or who have undergone long-term administration of corticosteroids, patients suffering from Cushing's syndrome, and patients having gonadal dysgenesis. Unchecked bone loss can lead to osteoporosis, a major debilitating disease whose prominent feature is the loss of bone mass (decreased density and enlargement of bone spaces) without a reduction in bone volume, producing porosity and fragility. Post-menopausal osteoporosis is associated with the large and rapid loss of bone mass due to the cessation of estrogen production by the ovaries. One source reports that ten million individuals in the United States are estimated to already have osteoporosis and almost 34 million more are estimated to have low bone mass, placing them at increased risk for the disease, and that one out of two women and one in eight men over age 50 will have an osteoporosis-related fracture in their lifetime.
PTH is involved in calcium and skeletal homeostasis. It stimulates the tubular resorption of calcium by the kidney and inhibits the reabsorption of phosphate and bicarbonate by the proximal renal tubules. PTH also affects the kidney by stimulating production of a vitamin D metabolite (1,25(OH)2D), which is an in vivo stimulator of osteoclasts and an enhancer of intestinal calcium absorption. The increase in intestinal calcium absorption following PTH stimulation is mediated by this vitamin D metabolite. In vivo, PTH stimulates osteoclastic bone resorption with the release of calcium into the circulation, and causes proliferation of osteoblasts.
With the general understanding of bone growth and its regulation, various approaches have been proposed to treat diseases involving reduction of bone mass and accompanying disorders by the administration of bone resorption inhibitors and/or anabolic agents, such as PTH. Examples of such approaches include U.S. Pat. No. 6,239,144 to Galvin et al., which discloses treating conditions associated with a lack of PTH by administering a compound having activity as a tachykinin receptor antagonist, which reportedly can increase the secretion of PTH; U.S. Pat. No. 5,670,514 to Audia et al., which discloses inhibiting bone loss by the administration of a 5α-reductase inhibitor (a benzoquinolin-3-one), alone or in combination with another bone anabolic agent, such as PTH; and U.S. Pat. No. 5,510,370 to Hock, which discloses treatment of bone loss in a patient by administering PTH sequentially, concurrently, or simultaneously with raloxifene.
It has been established that low dose, intermittent administration of PTH is associated with anabolic effects in humans, whereas higher dose, continuous administration of PTH is associated with catabolic effects. Rubin & Bilezikian, Int. J. Fertil. 47(3):103-15 (2002); Schaefer, Novartis Found Symp 227:225-39 (2000). U.S. Pat. No. 6,239,144 discloses that there is a dose dependent stimulation of the mineral apposition rate by PTH and that the result of the administration of PTH on skeletal homeostasis depends on how the hormone is administered. For the same daily dose, the bone volume shows a dose dependent increase if the daily dose of the hormone is given as one single injection. However, when the same daily dose is administered by continuous infusion with a subcutaneous mini-osmotic pump, the result is bone loss. Intermittent injection causes practically no effect on the serum calcium levels, whereas infusion causes a dose dependent increase in the serum calcium. The effects of PTH administered by these two routes on bone mineral apposition rate appeared to be the same. Once-daily injections are an undesirable means for the treatment and prevention of bone loss, because treatment and/or prophylaxis must occur over an extended period and frequent injections would be objectionable and would discourage patient compliance with the treatment. It would thus be desirable to provide alternative means for administering PTH intermittently, alone or in combination with other drugs useful in promoting bone growth and/or inhibiting bone loss.
There are myriad technologies generally referred to as providing controlled or sustained drug delivery, which deliver drug by a variety of routes. Although some controlled release methods and devices have been somewhat effective in controlling protein or peptide delivery in the body, several limitations can influence their suitability or practicality for administering a particular therapeutic agent, such as PTH. For example, many “controlled” release drug delivery systems may not provide a well-defined release profile. Other technologies may be suitable for continuous release (e.g., an ALZET™ osmotic pump), but not pulsatile release. Yet other technologies that are suitable for delivery of small molecule drugs would be unsuitable for long-term storage and delivery of fragile protein or peptide drug molecules. Such molecules may, for example, undergo degradation and denaturation associated with exposure to moisture, elevated temperatures (e.g., 37° C.), and/or by other means. Still other drug delivery systems undesirably would require periodic (frequent) replacement or refilling, or an unacceptably large size in order to provide for the administration of drug for long-term therapy.
It therefore would be desirable to provide a drug delivery system capable of accurately delivering a therapeutically and/or prophylactically effective amount of PTH, alone or in combination with other drugs. It desirably would provide well-defined pulsatile release of PTH over an extended period of time in a small, anatomically acceptable configuration, without requiring refilling of the delivery device with drug, repeated injections, or repeated replacement of part or the entire device over the course of treatment. In addition, it would be desirable for the drug delivery rate to be adjustable over the course of treatment.